Injection and injection kit containing omeprazole and its analogs

ABSTRACT

An injection solution comprising a 2-[(2-pyridyl)methylsulfinyl]-benzimidazole compound or a salt thereof having antiulcer activity and an aqueous solvent added with no nonaqueous solvent is disclosed wherein the pH is not less than 9.5 and not more than 11.5.

This application is a 371 of PCT/JP 93/00998 filed Jul. 15, 1993.

FIELD OF THE INVENTION

The present invention relates to an injection of a2-[(2-pyridyl)methylsulfinyl]benzimidazole compound or a salt thereofhaving antiulcer activity, particularly sodium salt of omeprazole and toan injection kit thereof, which are used in clinical fields.

BACKGROUND OF THE INVENTION

The 2-[(2-pyridyl)methylsulfinyl]benzimidazole compounds such asomeprazole or lansoprazole are potent antiulcer agents, and are used aspharmaceutical compositions for oral administration. Further, theinjections thereof have recently been developed.

As an injection of omeprazole, there has been known an injectionprepared by dissolving sodium salt of omeprazole in sterilized water,filtering and lyophilizing the solution to give a lyophilized product,and then dissolving the lyophilized product in a mixture of polyethyleneglycol 400 for injection, sodium dihydrogenphosphate and sterilizedwater (Japanese Patent Unexamined Publication No. 167587/1984).

Also, an injection prepared by dissolving a lyophilized product of analkaline aqueous solution of a2-[(2-pyridyl)methylsulfinyl]benzimidazole compound having antiulceractivity such as lansoprazole in a mixture of (a) acid, and (b) at leastone of ethanol, propylene glycol and polyethylene glycol (JapanesePatent Unexamined Publication No. 138213/1990).

In general, the pH of injection is preferably about 4-8, and a pH above9 has a probability of causing hemolysis and local irritation.

In the case of the 2-[(2-pyridyl)methylsulfinyl]benzimidazole compoundor a salt which may be hereinafter referred to as "benzimidazolecompound or salt thereof" represented by sodium salt of omepazole, itshows a solubility of the level permitting formulation of thepreparation, in water in an alkaline range of pH 9.5 or above, whereasit shows extremely low solubility in water at a pH of not more than 9,thus rendering formulation of the preparation very difficult.

While the benzimidazole compound or salt thereof is stable in thealkaline range, it poses a problem in that its stability decreases withthe low ph values.

For this reason, the method employed in conventional injections ofbenzimidazole compound or salt thereof such as sodium salt of omeprazolehas been to add an acid such as hydrochloric acid or sodiumdihydrogenphosphate to the solution to keep the pH from neutral to weakbasic, and to further add a nonaqueous solvent such as polyethyleneglycol, ethanol or propylene glycol in order to obtain a certain levelof solubility in such pH range.

Yet, these injections pose problems of local irritation and hemolysiscaused by the nonaqueous solvent added to the solution for dissolution.

Accordingly, an object of the invention is to provide an injection of abenzimidazole compound or a salt thereof, particularly sodium salt ofomeprazole causing less side-effects such as hemolysis, and less localirritation, which salt permits easy formulation.

SUMMARY OF THE INVENTION

As a result of the intensive study conducted by the inventors with theaim of achieving the aforementioned object, it has now been found that aproduct obtained by lyophilizing an alkaline aqueous solution ofbenzimidazole compound or salt thereof, and dissolving same in anaqueous solvent being devoid of nonaqueous solvent scarcely showshemolytic property and local irritation, notwithstanding the high pH offrom 9.5 to 11.5.

Accordingly, the present invention is:

(1) an injection comprising a 2-[(2-pyridyl)methylsulfinyl]benzimidazolecompound or a salt thereof having antiulcer activity and an aqueoussolvent devoid of nonaqueous solvent, which has a pH of not less than9.5 and not more than 11.5,

(2) an injection kit comprising the following (a) and (b), wherein (a)and (b) are adjusted such that the pH upon dissolution of (a) in (b) isnot less than 9.5 and not more than 11.5;

(a) : a lyophilized product of an alkaline aqueous solution of a2-[(2-pyridyl)methylsulfinyl]benzimidazole compound or a salt thereofhaving antiulcer activity

(b) : an aqueous solvent devoid of nonaqueous solvent.

DETAILED DESCRIPTION

The 2-[(2-pyridyl)methylsulfinyl]benzimidazole compounds havingantiulcer activity which are the element constituting the presentinvention include, for example, the compounds described in JapanesePatent Unexamined Publication No. 62275/1977, Japanese Patent UnexaminedPublication No. 1417/1979, Japanese Patent Unexamined Publication No.53406/1982, Japanese Patent Unexamined Publication No. 135881/1983,Japanese Patent Unexamined Publication No. 192880/1983, Japanese PatentUnexamined Publication No. 181277/1984 or Japanese Patent UnexaminedPublication No. 50978/1986, and omeprazole [chemical name:2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsulfinyl]-(5-methoxy)benzimidazole]and lansoprazole [chemical name:2-{2-[(3-methyl-4-(2,2,2-trifluoroethoxy)]-pyridylmethylsulfinyl}-benzimidazole]are exemplified.

As the salts of said benzimidazole compounds, for example, salts ofalkaline metal such as sodium salt or potassium salt or salts ofalkaline earth metal such as calcium salt or magnesium salt.

In view of the solubility, it is preferable for the present invention touse the salt of benzimidazole compound.

The injection of the present invention has a pH of not less than 9.5 andnot more than 11.5, preferably not less than 10 and not more than 11.Where the pH is less than 9.5, the benzimidazole compound or saltthereof does not sufficiently dissolve in an aqueous solvent and showspoor stability, while where it is more than 11.5, hemolytic property andlocal irritation become prominent.

According to the present invention, an injection of the benzimidazolecompound or salt thereof can be prepared by dissolving the benzimidazolecompound or salt thereof in water for injection, etc. along with astrong alkaline compound such as sodium hydroxide, potassium hydroxide,sodium carbonate or L-arginine, to give an alkaline aqueous solutionhaving a pH adjusted to not less than 10.5 and not more than 12.5,preferably not less than 11 and not more than 12. The alkaline aqueoussolution may contain mannitol, glycine, sorbitol, inositol, etc. ondemand for better forming of a lyophilized product.

The benzimidazole compound is contained in said alkaline aqueoussolution in a proportion of 1-50 mg/ml, preferably 5-40 mg/ml on a freecompound basis.

Then, this alkaline aqueous solution is filtered for sterilization, andcharged in a vial by 0.5-10 ml. After nitrogen gas displacement has beenpreformed as necessary, the solution is lyophilized by a method knownper se. The lyophilized product thus obtained is the (a): a lyophilizedproduct of an alkaline aqueous solution of the2-[(2-pyridyl)methylsulfinyl]benzimidazole compounds or salt thereofhaving antiulcer activity to be contained in the injection kit of thepresent invention.

When in use, the injection of the present invention can be produced bydissolving the lyophilized product thus obtained in an aqueous solventdevoid of nonaqueous solvent, such as physiological saline, aqueoussolution of 5% glucose, or distilled water for injection. Said aqueoussolvent corresponds to the (b): an aqueous solvent added with nononaqueous solvent to be contained in the injection kit of the presentinvention.

The injection of the present invention can be used, for example, in theform of drip infusion, intravenous injection, intramuscular injection,subcutaneous injection.

The concentration of benzimidazole compound in the injection of thepresent invention may vary depending upon the administration route, andgenerally ranges in a proportion of 0.05-10 mg/ml, preferably 0.1-5mg/ml on a free compound basis.

The benzimidazole compound in the injection of the present invention isadministered to an adult at 10-100 mg per day on a free compound basisin a single to three times divided doses, depending upon, for example,the symptoms of the patients.

BEST MODE FOR CARRYING OUT OF THE INVENTION EXPERIMENTAL EXAMPLE 1

Test preparation

1. Preparation obtained in Example 1 to be mentioned later

Test method

1. Hemolysis test

Hemolysis was evaluated by Akaishi method using whole blood of rabbit.The result is given in Table 1.

2. Local irritation test Local irritation was evaluated by thecomparison of necrotic muscular tissue area at the injection site in 3rabbits at 2 days after the administration of i ml of the testpreparation by intramuscular injection, with that in the rabbitsadministered with i ml of physiological saline or 1 ml of a 1.7% aceticacid solution, respectively by intramuscular injection.

The results are summarized in Table 2.

Test results

                  TABLE 1                                                         ______________________________________                                        Test preparation  pH     Hemolysis                                            ______________________________________                                        Ex. 1             10.5   not                                                                           observed                                             ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Test preparation pH     Necrotic area (mm.sup.2)                              ______________________________________                                        Ex. 1            10.5   63                                                    1.7% acetic acid --     398                                                   solution (positive                                                            comparison solution)                                                          physiological    --     31                                                    saline (negative                                                              comparison solution)                                                          ______________________________________                                    

(average of 3 rabbits)

The preparation of the present invention is desirable as an injection,since it does not cause hemolysis at all despite the high pH, and causesless local irritation,

EXAMPLE 1

1N Sodium hydroxide (2.3 ml) is added to 21.3 g of sodium salt ofomeprazole (20 g as omeprazole), and water for injection is addedthereto to adjust the pH to 11.5 and the total amount to 1 kg.

After filtration for sterilization, this alkaline aqueous solution ischarged in 10 ml vials by 2 g. A rubber plug is half driven in, andnitrogen displacement is performed. Lyophilization by a conventionalmethod and dissolution of the lyophilized product obtained in 10 ml ofphysiological saline give an omeprazole injection [4 mg (freecompound)/ml].

INDUSTRIAL APPLICABILITY

The injection of the present invention is void of the necessity to lowerpH so as to prevent hemolysis and local irritation, and to add anonaqueous solvent such as polyethylene glycol to an aqueous solvent fordissolution so as to prevent concomitant lowering of solubility. As aresult, irritation and hemolysis caused by the nonaqueous solvent can beavoided. Accordingly, the injection of the present invention can securesolubility sufficient for formulation into preparation and safety forthe human body.

We claim:
 1. An injection solution comprising a2-[(2-pyridyl)methylsulfinyl]benzimidazole compound or a salt thereofhaving antiulcer activity and an aqueous solvent devoid of nonaqueoussolvent, wherein the pH of the injection solution is not less than 9.5and not more than 11.5.
 2. The injection solution of claim 1, whereinthe 2-[(2-pyridyl)methylsulfinyl]benzimidazole compound or a saltthereof having antiulcer activity is in the form of a lyophilizedproduct of the alkaline aqueous solution dissolved in the aqueoussolvent devoid of nonaqueous solvent.
 3. The injection solution of claim1, wherein the 2-[(2-pyridyl)methylsulfinyl]benzimidazole salt is sodiumsalt of omeprazole.
 4. The injection solution of claim 1, wherein thebenzimidazole salt is selected from the group consisting of sodium,potassium, calcium, and magnesium.
 5. An injection kit comprising thefollowing components (a) and (b), in proportions such that the pH upondissolution of (a) in (b) is not less than 9.5 and not more than 11.5;the components being(a) : a lyophilized product of an alkaline aqueoussolution of a 2-[(2-pyridyl)methylsulfinyl]benzimidazole compound or asalt thereof having antiulcer activity (b) : an aqueous solvent devoidof nonaqueous solvent.
 6. The injection kit of claim 5, wherein the2-[(2-pyridyl)methylsulfinyl]benzimidazole salt is sodium salt ofomeprazole.